造血细胞特异性鸟苷酸交换因子Vav1在T细胞及癌细胞中的作用机制探讨

Vav proteins are guanine nucleotide exchange factors (GEF) for Rho family small GTPases. There are three members, Vav1 is restrictively expressed in hematopoietic cells such as T cell, B cells, etc., while Vav2 and Vav3 are ubiquitously expressed. Although redundancy was discussed in their substrate (GTPases) specificity as GEFs, Vav1 plays irreplacable role in T cell receptor mediated signal transduction, especially in the axis of calcium/calmodulin-calcineurin-NFAT signal pathway. Accumulating evidence revealed that Vav1 is surprisingly detected in non-hematopoietic tumor cells and tissue specimens, which is in good correlation with malignancy and poor prognosis. The most recent studies also implied that demethylation of vav1 gene promoter may lead to the transcription of Vav1 in malignant cells, further suggesting that the methylation level of vav1 promoter can be used as an epigenetic marker. Therefore, Vav1 possesses functions distinct from the other two members, Vav2 and Vav3. As there haven't been any natural mutations of Vav1 discovered, the aberrant expression and the amount of Vav1 may attribute to human malignancy and poor diagnosis. In this study, we aim to identify the distinct function(s) of Vav1 (from Vav2 and Vav3), and to explore the new mechanisms of Vav1 involved in T cell activation and apoptosis, and in tumor cell growth and migration by using controllable expression systems. This study will provide new insight into cancer biology and may lead to the new anti-cancer strategy.

Vav蛋白是一类Rho家族小G蛋白鸟苷酸交换因子，催化GDP结合的小G蛋白转化为GTP结合的活性形式。其中Vav1的表达仅限于造血细胞，如T和B淋巴细胞，在T细胞的发育、成熟和细胞受体（TCR）介导的信号转导中起重要作用；其哺乳动物的同源物Vav2和Vav3广泛表达于各类组织细胞中。虽然三种Vav在活化小G蛋白底物的功能上有一定的互补性，但Vav1的缺失降低了T细胞的受体激活的反应强度，特别是钙离子参与的激活转录因子等事件。最近发现Vav1在非造血系的肿瘤细胞中也有表达，其表达与肿瘤恶性程度呈正相关。这都表明Vav1具有区别于Vav2/3的特殊功能，而其异常的组织分布以及表达量可能是肿瘤发生恶化和不良预后的重要因素。本项目以Vav1在T细胞系中表现的Vav2和3不可替代的功能为出发点，建立可控性Vav1表达系统，探究其在T细胞以及癌细胞中的作用机制，为治疗和干预癌症提供新的策略和理论依据。

Vav蛋白是一类Rho家族小G蛋白鸟苷酸交换因子，催化GDP结合的小G蛋白转化为GTP结合的活性形式。其中Vav1的表达仅限于造血细胞，如T和B淋巴细胞，在T细胞的发育、成熟和细胞受体（TCR）介导的信号转导中起重要作用；其哺乳动物的同源物Vav2和Vav3广泛表达于各类组织细胞中。Vav1的N-20片段通过赋予其与CaM结合的特性，区别于同族的Vav2和Vav3，在T细胞钙信号通路甚至T细胞激活过程中发挥不可或缺的功能。最近发现Vav1在非造血系的肿瘤细胞中也有表达，其表达与肿瘤恶性程度呈正相关。这都表明Vav1具有区别于Vav2/3的特殊功能，而其异常的组织分布以及表达量可能是肿瘤发生恶化和不良预后的重要因素。基于此，我们发现，雌激素以及其受体调节Vav1的转录和表达，部分参与了癌细胞的增殖。本项目以Vav1在T细胞系中表现的Vav2和3不可替代的功能为出发点，建立可控性Vav1表达系统，探究其在T细胞以及癌细胞中的作用机制，为治疗和干预癌症提供新的策略和理论依据。